# US 10,308,661 B2 · Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides

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- Number: US 10,308,661 B2
- Document ID: US10308661B2
- Status: Granted
- Kind: B2
- Application number: 15/571,921
- Filed: 2016-05-09
- Published: 2018-05-03
- Granted: 2019-06-04
- Earliest claimed: 2015-05-07
- Assignees: Eisai R&D Management Co., Ltd.
- Applicants: Eisai R&D Management Co., Ltd.
- Inventors: Francis G. Fang; Dae-Shik Kim; Hyeong-Wook Choi; Charles E. Chase
- Web page: https://patentgrep.com/patent/US10308661B2

## CPC

- C07D 493/22: in which the condensed system contains four or more hetero rings
- C07F 9/6552: {the oxygen atom being part of a six-membered ring}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The invention provides methods for the synthesis of a halichondrin macrolides through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Homer-Wadsworth-Emmons olefination), catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic macrolide. The invention also provides compounds useful as intermediates in the synthesis of a halichondrin macrolides and methods for preparing the same.

## Claims

### Claim 1

A method of preparing a macrocyclic intermediate in the synthesis of a halichondrin macrolide, said method comprising performing a macrocyclization reaction on a non-macrocyclic intermediate, said macrocyclization reaction producing said macrocyclic intermediate by forming C.2-C.3, C.3-C.4, C.12-C.13, C.15-C.16, C.19-C.20, or C.26-C.27 bond in the structure of the halichondrin macrolide.

### Claim 2 (depends on 1)

The method of claim 1, wherein said performing said macrocyclization reaction comprises contacting said non-macrocyclic intermediate with an organic base and a Lewis acid, contacting said non-macrocyclic intermediate with an olefin metathesis catalyst, or contacting said non-macrocyclic intermediate with a Cr(II) salt and a Ni(II) salt.

### Claim 3 (depends on 2)

The method of claim 2, wherein said non-macrocyclic intermediate is (1) a compound of formula (IA):
or a salt or a tautomer thereof,
wherein
each R is independently optionally substituted alkyl or optionally substituted aryl;
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group; and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (IB):
or a salt or a tautomer thereof;
and said performing said macrocyclization reaction comprises contacting said compound of formula (IA) or a salt or a tautomer thereof with an organic base and a Lewis acid;
(2) a compound of formula (IIA):
or a salt or a tautomer thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is
attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein Py is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group; and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (IB):
or a salt or a tautomer thereof;
and said performing said macrocyclization reaction comprises contacting said compound of formula (IIA) or a salt or a tautomer thereof with an olefin metathesis catalyst;
(3) a compound of formula (IIIA):
or a salt or a tautomer thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group; and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (IlIB):
or a salt or a tautomer thereof;
and said performing said macrocyclization reaction comprises contacting said compound of formula (IIIA) or a salt or a tautomer thereof with an olefin metathesis catalyst;
(4) a compound of formula (IVA):
or a salt thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R2 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
(i) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(ii) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(iii) R3 and R4 combine to form a bond, and R5 is H;
each P4 and P5 is independently H or a hydroxyl protecting group;
R6 is H, and P6 is H or a hydroxyl protecting group; or R6 and P6 combine to form a double bond; and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (IVB):
or a salt thereof;
and said performing said macrocyclization reaction comprises contacting said compound of formula (IVA) or a salt thereof with an olefin metathesis catalyst;
(5) a compound of formula (VA):
or a salt or a tautomer thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
(a1) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(a2) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(a3) R3 and R4 combine to form a bond, and R5 is H;
(b1) A1 and R7 combine to form oxo, R6 is H or a hydroxyl protecting group, and R8 is H;
or
(b2) A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R6 is H or a hydroxyl protecting group, and R7 and R8 combine to form a double bond;
or
(ii) R6 and R7 combine to form a bond, and R8 is H or OP″;
(c1) R9 is H, and P4 is H or a hydroxyl protecting group;
or
(c2) R9 and P4 combine to form a double bond;
R10 is H or —CH2X1CH2CH═CH2 , wherein X1 is O, —C(R11)2—, or NP6, and wherein each R11 is independently H or —COOR12, P6 is an N-protecting group, and R12 is alkyl;
each P5 is independently H or a hydroxyl protecting group; and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (VB):
or a salt or a tautomer thereof;
and said performing said macrocyclization reaction comprises contacting said compound of formula (VA) or a salt or a tautomer thereof with an olefin metathesis catalyst;
(6) a compound of formula (VIA):
or a salt or a tautomer thereof,
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
b designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or b designates (S)-stereogenic center, and Z is OR6, wherein R6 is a hydroxyl protecting group;
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3 and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (IVB):
or a salt or a tautomer thereof,
wherein
b designates (R)-stereogenic center, c designates (S)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or
b designates (S)-stereogenic center, c designates (R)-stereogenic center, and Z is OR6,
wherein R6 is a hydroxyl protecting group;
and said performing said macrocyclization reaction comprises contacting said compound of formula (VIA) or a salt or a tautomer thereof with a Cr(II) salt and a Ni(II) salt; or
(7) a compound of formula (VIIA):
or a salt thereof,
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
(a1) R3 is H or a hydroxyl protecting group, R4 and R5 combine to form a double bond, each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—, wherein R8 is H or a hydroxyl protecting group;
or
(a2) R3 and R4 combine to form a bond, R5 is H, and
each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(b1) Z is chloride, bromide, or iodide, and R6 and R7 combine to form a bond;
or
(b2) Z and R7 combine to form a double bond, and R6 is a hydroxyl protecting group;
and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (VIIB):
or a salt thereof,
wherein each of P5 and R6 is independently H or a hydroxyl protecting group;
and said performing said macrocyclization reaction comprises contacting said compound of formula (VIIA) or a salt thereof with a Cr(II) salt and a Ni(II) salt.

### Claim 4 (depends on 3)

The method of claim 3, wherein for (1),
(a) each R is optionally substituted alkyl;
(b) both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(c) P5 is a hydroxyl protecting group;
(d) R3 and R4 combine to form a bond, and R5 is H;
(e) said organic base is DBU or trimethylamine; and/or
(f) said Lewis acid is a salt of Li or Zn.

### Claim 5 (depends on 3)

The method of claim 3, wherein for (2) or (3),
(a) both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and/or
(b) P5 is a hydroxyl protecting group.

### Claim 6 (depends on 3)

The method of claim 3, wherein for (4), at least one of P4 and P5 is H.

### Claim 7 (depends on 3)

The method of claim 3, wherein for (5),
(a) R9 is H, and P4 is H;
(b) R10 is —CH2X1CH2CH═CH2, and X1 is O;
(c) R6 and R7 combine to form a bond, and R8 is H;
(d) each P5 is independently a hydroxyl protecting group
(e) at least one P5 is H; and/or
(f) R3 and R4 combine to form a bond, and R5 is H.

### Claim 8 (depends on 3)

The method of any one of claims 3, wherein for (2), (3), (4), or (5), said olefin metathesis catalyst is a ruthenium-carbene complex.

### Claim 9 (depends on 3)

The method of claim 3, wherein for (6),
(a) Y is bromide;
(b) R3 and R4 combine to form a bond, and R5 is H;
(c) both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(d) Z is a sulfonate;
(e) Z is OR6, wherein R6 is a hydroxyl protecting group; and/or
(f) Z is an ester, carbonate, or carbamate.

### Claim 10 (depends on 3)

The method of claim 3, wherein for (7),
(a) Z is iodide;
(b) Y is trifluoromethanesulfonate;
(c) R3 is H or a hydroxyl protecting group, R4 and R5 combine to form a double bond, each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms —(CH(OR8))—, wherein R8 is H or a hydroxyl protecting group;
(d) at least one of P3 P4, and R6 is a hydroxyl protecting group; and/or
(e) Z is chloride, bromide, or iodide, and R6 and R7 combine to form a bond.

### Claim 11

A method of preparing:
or a salt thereof,
wherein
each of A1 and A2 is independently H or OP″, where each P″ is independently H or a hydroxyl protecting group;
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
(1) said method comprising:
(A) producing a compound of formula (IB) from a compound of formula (IA), the compound of formula (IA) having the following structure:
or a salt or a tautomer thereof,
wherein
each R is independently optionally substituted alkyl or optionally substituted aryl;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group; and
the compound of formula (IB) having the following structure:
or a salt or a tautomer thereof;
and
(B) producing the halichondrin macrolide from compound (IB);
(2) said method comprising:
(A) producing a compound of formula (IB) from a compound of formula (IIA), the compound of formula (IIA) having the following structure:
or a salt or a tautomer thereof,
wherein
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group; and
The compound of formula (IB) haying the following structure:
or a salt or a tautomer thereof;
and
(B) producing the halichondrin macrolide from compound (IB);
(3) said method comprising:
(A) producing a compound of formula (IIIB) from a compound of formula (IIIA), the compound of formula (IIIA) haying the following structure:
or a salt or a tautomer thereof,
wherein
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond:
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group; and
the compound of formula (IIIB) having the following structure:
or a salt or a tautomer thereof;
and
(B) producing the halichondrin macrolide from the compound of formula (IIIB):
(4) said method comprising:
(A) producing a compound of formula (IVB) from a compound of formula (IVA), the compound of formula (IVA) having the following structure:
or a salt thereof,
wherein
(i) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(ii) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(iii) R3 and R4 combine to form a bond, and R5 is H;
each P4 and P5 is independently H or a hydroxyl protecting group;
R6 is H, and P6 is H or a hydroxyl protecting group; or R6 and P6 combine to form a double bond; and
the compound of formula (IVB) haying the following structure:
or a salt thereof;
and
(B) producing the halichondrin macrolide from the compound of formula (IVB);
(5) said method comprising:
(A) producing a compound of formula (VB) from a compound of formula (VA), the compound of formula (VA) haying the following structure:
or a salt or a tautomer thereof,
wherein
(a1) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(a2) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(a3) R3 and R4 combine to form a bond, and R5 is H;
(b1) A1 and R7 combine to form oxo, R6 is H or a hydroxyl protecting group, and R8 is H;
or
(b2) A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R6 is H or a hydroxyl protecting group, and R7 and R8 combine to form a double bond;
or
(ii) R6 and R7 combine to form a bond, and R8 is H or OP″;
(c1) R9 is H, and P4 is H or a hydroxyl protecting group;
or
(c2) R9 and P4 combine to form a double bond;
R10 is H or —CH2X1CH2CH═CH2 , wherein X1 is O, —C(R11)2—, or NP6, and wherein each R11 is independently H or —COOR12, P6 is an N-protecting group, and R12 is alkyl;
each P5 is independently H or a hydroxyl protecting group; and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (VB):
or a salt or a tautomer thereof;
(B) producing a compound of formula (VC) from the compound of formula (VB), the compound of formula (VC) having the following structure:
or a salt thereof,
wherein each of A1 and A2 is independently H or OP″;
(C) producing a compound of formula (IVC) from the compound of formula (VC), the compound of formula (IVC) haying the following structure:
or a salt thereof,
wherein each of A1 and A2 is independently H or OP″; and
(D) producing the halichondrin macrolide from the compound of formula (IVC);
(6) said method comprising:
(A) producing a compound of formula (VIB) from a compound of formula (VIA), the compound of formula (VIA) haying the following structure:
or a salt or a tautomer thereof,
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
b designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or b designates (S)-stereogenic center, and Z is OR6, wherein R6 is a hydroxyl protecting group;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
and each P4 is independently H or a hydroxyl protecting group, and X1 is oxo; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
the compound of formula (VIB) having the following structure:
or a salt or a tautomer thereof,
wherein
b designates (R)-stereogenic center, c designates (S)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or
b designates (S)-stereogenic center, c designates (R)-stereogenic center, and Z is OR6,
wherein R6 is a hydroxyl protecting group;
(B) producing the halichondrin macrolide from the compound of formula (VIB); or
(7) said method comprising:
(A) producing a compound of formula (VIIB) from a compound of formula (VIIA), the compound of formula (VIIA) having the following structure:
or a salt thereof,
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
(a1) R3 is H or a hydroxyl protecting group, R4 and R5 combine to form a double bond, each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
(a2) R3 and R4 combine to form a bond, R5 is H, and
each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(b1) Z is chloride, bromide, or iodide, and R6 and R7 combine to form a bond;
or
(b2) Z and R7 combine to form a double bond, and R6 is a hydroxyl protecting group;
and
wherein R8 is H or a hydroxyl protecting group
the compound of formula (VIIB) having the following structure:
or a salt thereof,
wherein each of P5 and R6 is H or a hydroxyl protecting group;
(B) producing a compound of formula (VIIC) from the compound of formula (VIIB), the compound of formula (VIIC) having the following structure:
or a salt or a tautomer thereof,
wherein A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
(C) producing a compound of formula (VIID) from the compound of formula (VIIC), the compound of formula (VIID) having the following structure:
or a salt thereof,
wherein each of A1 and A2 is independently H or OP″;
and
(D) producing the halichondrin macrolide from the compound of formula (VIID).

### Claim 12 (depends on 11)

The method of claim 11, wherein for (1),
(a) said producing the compound of formula (IB) comprises reacting the compound of formula (IA) with an organic base and a Lewis acid;
(b) said producing the halichondrin macrolide comprises reacting the compound of formula (IB) with a hydroxyl protecting group removing agent; and/or
(c) each R is optionally substituted alkyl.

### Claim 13 (depends on 11)

The method of claim 11, wherein for (2)
(a) said producing the compound of formula (IB) comprises reacting the compound of formula (IIA) with an olefin metathesis catalyst; and/or
(b) said producing the halichondrin macrolide comprises reacting the compound of formula (IB) with a hydroxyl protecting group removing agent.

### Claim 14 (depends on 11)

The method of claim 11, wherein for (3)
(a) said producing the compound of formula (IIIB) comprises reacting the compound of formula (IIIA) with an olefin metathesis catalyst;
(b) said producing the halichondrin macrolide comprises reacting the compound of formula (IIIB) with a hydroxyl protecting group removing agent;
(c) both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and/or
(d) P5 is a hydroxyl protecting group.

### Claim 15 (depends on 11)

The method of claim 11, wherein for (4)
(a) said producing the compound of formula (IVB) comprises reacting the compound of formula (IVA) with an olefin metathesis catalyst;
(b) said producing the halichondrin macrolide from the compound of formula (IVB) comprises reacting the compound of formula (IVB) with a Brønsted acid; and/or
(c) at least one of P4 and P5 is H.

### Claim 16 (depends on 11)

The method of claim 11, wherein said producing the halichondrin macrolide comprises producing the compound of formula (IVC), the compound of formula (IVC) having the following structure:
or a salt thereof,
wherein each of A1 and A2 is H or OP″, and wherein P″ is H or a hydroxyl protecting group;
and producing the halichondrin macrolide from the compound of formula (IVC).

### Claim 17 (depends on 16)

The method of claim 16, wherein
(a) said producing the compound of formula (IVC) comprises reacting the compound of formula (IVB) with a hydroxyl protecting group removing agent; and/or
(b) said producing the halichondrin macrolide from the compound of formula (IVC) comprises reacting the compound of formula (IVC) with a Brønsted acid.

### Claim 18 (depends on 11)

The method of claim 11, wherein for (5),
(a) said producing the compound of formula (VB) comprises contacting the compound of formula (VA) with an olefin metathesis catalyst
(b) P4 is H, R9 is H, and said producing the compound of formula (VC) comprises oxidizing the compound of formula (VB) to produce a compound of formula (VBa):
or a salt thereof;
and reacting the compound of formula (VBa) with a 1,4-reducing agent to produce the compound of formula (VC);
(c) said producing the compound of formula (IVC) comprises contacting the compound of formula (VC) with a hydroxyl protecting group removing agent; and/or
(d) said producing the halichondrin macrolide comprises contacting the compound of formula (IVC) with a Brønsted acid.

### Claim 19 (depends on 11)

The method of claim 11, wherein for (6),
(a) said producing the compound of formula (VIB) comprises reacting the compound of formula (VIA) with a Cr(II) salt and a Ni(II) salt;
(b) said producing the halichondrin macrolide comprises the step of nucleophilic ring-closing of the compound of formula (VIB);
(c) wherein both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and/or
(d) R3 and R4 combine to form a bond, and R5 is H.

### Claim 20 (depends on 11)

The method of claim 11, wherein for (7),
(a) said producing the compound of formula (VIIB) comprises reacting the compound of formula (VIIA) with a Cr(II) salt and a Ni(II) salt:,
(b) said producing the compound of formula (VIIC) comprises the step of nucleophilic ring-closing of the compound of formula (VIIB);
(c) said producing the compound of formula (VIID) comprises reacting the compound of formula (VIIC) with a hydroxyl protecting group removing agent;
(d) said producing the halichondrin macrolide comprises reacting the compound of formula (VIID) with a Brønsted acid;
(e) Z is iodide;
(f) Y is trifluoromethanesulfonate;
(g) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
(h) each P4 is independently H or a hydroxyl protecting group, and
X1, together with the carbon to which it is attached, forms —CH(OR8))—, wherein R8 is H or a hydroxyl protecting group;
(i) P5 is H; and/or
(j) Z is chloride, bromide, or iodide, and R6 and R7 combine to form a bond.

### Claim 21 (depends on 3)

The method of claim 3, wherein
(a) designates (S)-stereogenic center;
(b) one and only one of D and D′ is optionally substituted alkyl or OP1;
(c) A is a group of formula (1);
(d) L is —(CH(OP2))—;
(e) R1 and P1 combine to form a bond;
(f) G is O;
(g) E is optionally substituted alkyl;
(h) k is 1;
(i) R2 is —(CH2)nOP3;
(j) at least one of P2 and P3 is a hydroxyl protecting group; and/or
(k) A1 is H.

### Claim 22 (depends on 21)

The method of claim 21, wherein one and only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group.

### Claim 23

A method of preparing an intermediate in the synthesis of a halichondrin macrolide, said method comprising performing an allene-Prins reaction by contacting a compound of formula (VIIIA) with a compound of formula (VIIIB) and R4OH,
wherein R4 is an optionally substituted acyl;
wherein the compound of formula (VIIIA) has the following structure:
or a salt thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
X is O, or X, together with the carbon atom to which it is attached, forms —(C(OPZ)2)—, wherein each PZ is independently optionally substituted alkyl or optionally substituted aryl, or both PZ combine to form optionally substituted alkylene or optionally substituted arylene; and
P4 is H or a hydroxyl protecting group;
wherein the compound of formula (VIIIB) has the following structure:
wherein
R3 is —CH2—OP5, —CH═CH2,
wherein P5 is H or a hydroxyl protecting group; each P6 is independently a hydroxyl protecting group, or both P6 groups, together with the atoms to which each is attached, combine to form a cyclic protected diol; and R5 is H or —CH2X1CH2CH═CH2, wherein X1 is O, —CH2—, or NP7, wherein P7 is a sulfonyl;
and wherein said intermediate is a compound of formula (VIIIC):
or a salt thereof.

### Claim 24 (depends on 23)

The method of claim 23, wherein said performing a Prins reaction comprises reacting the compound of formula (VIIIA) with a Lewis acid; and/or k is 1.

### Claim 25

A compound of
(1) formula (IA) or formula (IB),
or a salt or a tautomer thereof,
wherein
each R is independently optionally substituted alkyl or optionally substituted aryl;
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H,
optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group;
(2) formula (IIA), formula (IIIA), or formula (IIIB):
or a salt or a tautomer thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group: A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) haying the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each a is independently ORA SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal; and
P5 is H or a hydroxyl protecting group;
(3) formula (IVA), formula (IVB), or formula (IVC):
or a salt thereof,
wherein
each of A1 and A2 is H or OP″, where P″ is H or a hydroxyl protecting group;
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
(i) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(ii) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(iii) R3 and R4 combine to form a bond, and R5 is H;
each P4 and P5 is independently H or a hydroxyl protecting group; and
R6 is H, and P6 is H or a hydroxyl protecting group; or R6 and P6 combine to form a double bond;
(4) formula (VA), formula (VB), or formula (VC):
or a salt or a tautomer thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
A2 is H or OP″;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
(a1) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(a2) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(a3) R3 and R4 combine to form a bond, and R5 is H;
(b1) A1 and R7 combine to form oxo, R6 is H or a hydroxyl protecting group, and Rs is H;
or
(b2) A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R6 is H or a hydroxyl protecting group, and R7 and R8 combine to form a double bond;
or
(ii) R6 and R7 combine to form a bond, and R8 is H or OP″;
(c1) R9 is H, and P4 is H or a hydroxyl protecting group;
or
(c2) R9 and P4 combine to form a double bond;
R10 is H or —CH2X1CH2CH═CH2 wherein X1 is O, —C(R11)2—, or NP6, and wherein each R11 is independently H or —COOR12 P6 is an N-protecting group, and R12 is alkyl;
each P5 is independently H or a hydroxyl protecting group;
(5) formula (VIA):
or a salt or a tautomer thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
Y is iodide, bromide, or trifluoromethanesulfonate;
b designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or b designates (S)-stereogenic center, and Z is OR6, wherein R6 is a hydroxyl protecting group;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(6) formula (VIB):
or a salt or a tautomer thereof,
wherein
b designates (R)-stereogenic center, c designates (S)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or
b designates (S)-stereogenic center, c designates (R)-stereogenic center, and Z is OR6,
wherein R6 is a hydroxyl protecting group;
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2) nOP3 and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(7) formula (VIIA) or formula (VIIB):
or a salt thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3 and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
(a1) R3 is H or a hydroxyl protecting group, R4 and R5 combine to form a double bond, each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
(a2) R3 and R4 combine to form a bond, R5 is H, and
each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(b1) Z is chloride, bromide, or iodide, and R6 and R7 combine to form a bond;
(b2) Z and R7 combine to form a double bond, and R6 is a hydroxyl protecting group;
or
(b3) when Z and R7 are absent, R6 is H or a hydroxyl protecting group;
P5 is H or a hydroxyl protecting group;
wherein R8 is H or a hydroxyl protecting group; or
(8) formula (VIIC):
or a salt or a tautomer thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
each P4 is H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group; or both P4 groups and X1, together with the atoms to which each is attached, combine to form a ketal; and
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″.

### Claim 26

A compound of formula (VIIC):
or a salt thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group; A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
wherein
L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
R1 is H, or R1 and P1 combine to form a bond;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
wherein each P′ is independently H or a hydroxyl protecting group;
E is optionally substituted alkyl or optionally substituted alkoxy;
G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
k is 0 or 1;
n is 0, 1, or 2;
P4 is H or a hydroxyl protecting group; and
R3 is —CH2OP5, —CH═CH2,
wherein P5 is H or a hydroxyl protecting group; each P6 is independently a hydroxyl protecting group, or both P6 groups, together with the atoms to which each is attached, combine to form a cyclic protected diol; and R5 is H or —CH2X1CH2CH═CH2, wherein X1 is O, —CH2—, or NP7, wherein P7 is a sulfonyl.